Autocrine GDF10 Inhibits Hepatic Stellate Cell Activation via BMPR2/ALK3 Receptor to Prevent Liver Fibrosis
Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis, and their activation is controlled by a complex interplay of autocrine/paracrine signals within the liver microenvironment. Here, we show that growth differentiation factor 10 (GDF10) is specifically expressed by HSCs in both mouse and human livers, and its expression is reduced in activated HSCs. Loss of GDF10 function promotes HSC activation and exacerbates liver fibrosis in mice, while gain of GDF10 function alleviates this pathological condition. Mechanistically, autocrine GDF10 binds to BMPR2/ALK3 receptor to elicit SMAD1/5/8-SMAD7 signaling pathway in HSCs. Activated SMAD1/5/8-SMAD7 signaling pathway then inhibits the TGF-β-SMAD2/3 signaling transduction, which is essential for HSC activation. Moreover, recombinant GDF10 protein treatment suppresses HSC activation and alleviates liver fibrosis in mice. In conclusion, GDF10 is an autocrine suppressor of HSC activation and a potential therapeutic target for the treatment of liver fibrosis.
Authors
- Heng Fan (ORCID: https://orcid.org/0009-0006-8763-1383)
- Yuhui Li (ORCID: https://orcid.org/0000-0002-5794-8172)
- Ping Qiu (ORCID: https://orcid.org/0009-0004-9350-3383)
- Wei Qiao (ORCID: https://orcid.org/0000-0001-5287-9916)
- Sufang Sheng
- Zuoyu Chen
- Zemin Pan (ORCID: https://orcid.org/0000-0001-5833-0369)
- Yongsheng Chang (ORCID: https://orcid.org/0000-0002-7846-8127)
- Xiaochen Gai (ORCID: https://orcid.org/0000-0002-6435-1753)
- Chunyuan Du
- Min Liu (ORCID: https://orcid.org/0000-0001-5183-1187)
- Xiaorong Li (ORCID: https://orcid.org/0000-0003-0641-2797)
- Yujie Zhang (ORCID: https://orcid.org/0000-0002-4686-6526)
- Xi Zhang (ORCID: https://orcid.org/0000-0003-2859-7438)
- Jun Zhang (ORCID: https://orcid.org/0000-0002-4321-8080)
- Yinliang Zhang
- Jingran Hao
Institutions
- Shihezi University (CN)
- Tianjin Medical University General Hospital (CN)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Westlake University (CN)
- Second Hospital of Shandong University (CN)
- Ningxia Medical University (CN)
- Tianjin Medical University Eye Hospital (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1002/advs.202500616
- Citations
- 4
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 5.29
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China